Outline

Material and Methods: Adult female C3H mice were treated with single-fraction radiotherapy (RT) to the right kidney with doses of 6-17 Gy and with or without IGF-1 or EPO. The kidney function was assessed prior to RT, 19 weeks thereafter and then every 6 weeks by 99mTc-dimercaptosuccinat scans (static scintigraphy, maximum follow-up 49 weeks). IGF-1 was given subcutaneously either concomitant to RT or after 5-6 months. Delayed treatment after deterioration of the kidney function was administered over 4 weeks, immediately followed by repeat scans every 6 weeks. Doses of IGF-1 were 0.5-25 mg per injection. EPO was given concomitant to RT in a dose of 500 IU or 2000 IU/kg body weight.

Results: The function of the irradiated kidney continuously declined during follow-up in all control groups in a dose-dependent fashion. Very accurate and reproducible results were obtained when scintigraphy was repeatedly performed in the same control animals before kidney dysfunction developed. Concomitant treatment with 15 Gy and IGF-1 significantly reduced the number of mice with a severe decline, defined as loss of function of 50% or more. In contrast to controls, no statistically significant decline of the mean kidney function was observed in the best IGF-1 group. The best dose of IGF-1 was 5 mg per injection, administered over 2 weeks. Delayed treatment after deterioration of the kidney function was unable to restore it, regardless of the IGF-1 dose. Very few animals in the groups with delayed IGF-1 showed at least stabilisation of the compromised kidney function. EPO actually increased the degree of radiation nephropathy. The higher dose of EPO caused more damage than the lower dose.

Conclusions: We have developed an accurate, reliable method for screening of response modifiers. Our results show that administration of growth factors concomitant to RT causes profound alterations in the development of kidney dysfunction. Surprisingly, EPO increased the loss of function, whereas IGF-1 acted as a protective agent after high-dose irradiation. We have examined the IGF-1 dose-response in order to define the optimum treatment schedule. Established nephropathy did not improve after prolonged administration of IGF-1, suggesting that early intervention might be the preferable approach.